PROJECTSUMMARY/ABSTRACT Imbalancebetweengoal-directed(GD)andhabitual(H)behaviorplaysacentralroleintheetiologyof substanceusedisorder(SUD)1,2.Thesebehaviorsareregulatedbydistinctfrontostriatalregions3,4:orbitofrontal cortex(OFC)5,ventromedialprefrontalcortex(vmPFC)6,dorsolateralprefrontalcortex(dlPFC)7,andtherostral medialstriatum(rMS)forGDbehavior;?premotorcortex(PM)6,supplementarymotorarea(SMA)8,andthecaudal lateralstriatum(cLS)forHbehavior.Furthermore,recentworkdemonstratesacentralrolefortheventrolateral prefrontalcortex(vlPFC)inarbitratingwhetherbehaviorisunderthecontroloftheGDorHsysteminagiven situation and facilitating transitions between the two behaviors9,10. Elucidating the anatomy underlying this circuitryiscriticaltofurtheringinsightsabouttheneuralbasisofmaladaptivehabitformationinaddiction.The firstgoalofthesestudiesistoidentifythecorticostriatalanatomicalsubstratesthatareinapositiontoa)integrate themultiplefunctionalinputsneededforGDandHbehavior,respectively,andb)facilitatetransitionsbetween the two behaviors. The second goal of these studies is to examine how these substrates may be aberrant in SUD patients. Aim 1 will use anterograde anatomical tract-tracing in non-human primates (NHPs) to identify candidatesubstrates,bylocatingareasofthestriatumwherethecorticalprojectionsforeachbehaviorconverge;? Aim2willuseretrogradeanatomicaltract-tracinginNHPstocorroboratethefrontostriatalconnectionsfoundin Aim1andwillquantifytheirstrength.Aim3willthena)useanatomy-guidedfunctionalconnectivityMRI(fcMRI) tolocalizetheseanatomicalsubstratesinhumansandb)assesshowfunctionalconnectivityamongstthesekey anatomicalsubstratesisunbalancedinSUDpatients. Recent work from our lab has identified loci in the striatum that receive disproportionately numerous inputs from functionally diverse prefrontal regions11,12, referred to as hubs. Hubs are areas of unusually high connectivitytootherbrainregionsandarethoughttobecentralforintegratinganddistributinginformationacross multiple,diverseregions13,14.WehypothesizethatH1.OFC,vmPFC,dlPFCandvlPFCprojectionsformahub intherMS,andthatPM,SMAandvlPFCprojectionsformahubinthecLS,representingpotentialanatomical substratestointegratetheinputsneededforGDandHbehavior,respectively.Asacorollary,wehypothesize thatH2.thevlPFChasprojectionstoboththeGDandHstriatalhubs,representinganatomicalsubstratesthat could allow vlPFC arbitration of transitions between the two behaviors. Finally, we hypothesize that H3. SUD patients - who exhibit an overreliance on H behavior2,15 - will have an abnormal ratio of vlPFC-rMS functional connectivitytovlPFC-cLSfunctionalconnectivitycomparedtohealthymatchedcontrols.Overall,thisresearch will provide new insights about the location and nature of key circuitry components that may contribute to maladaptive habit formation in addiction, and which may also be applicable to disorders such as obsessive- compulsivedisorderandTourette'ssyndrome.